Fosfomycin pharmaceutical composition

ABSTRACT

The present invention relates to a solid fosfomycin pharmaceutical composition stable in front the coloration, suitable for diabetics and not entailing gastrointestinal problems. 
     The pharmaceutical composition of this invention comprises fosfomycin trometamol, glycine, and optionally other excipients as sucralose, silice dioxide, polyvinylpyrrolidone and flavor; and is substantially free from sugars and sugar alcohols as sucrose, fructose, glucose, xylitol, mannitol, sorbitol or mixtures thereof.

TECHNICAL FIELD

The present invention relates to a stable pharmaceutical composition fororal administration of the antibiotic fosfomycin.

BACKGROUND ART

Fosfomycin trometamol, which chemical name ismono(2-ammonium-2-hydroxymethyl-1,3-propanediol)(2R,cis)-(3-methyloxiranyl)phosphonate, is an antibiotic indicated inthe prophylaxis and treatment of uncomplicated acute infections of thelower urinary tract.

There are some fosfomycin trometamol pharmaceutical compositions fororal administration disclosed in the state of the art.

The Spanish patent application ES495870 (Zambon, S.p.a.) describes acomposition for oral administration in form of sachets containingfosfomycin trometamol, sodium carboxymethylcellulose, lactose, titaniumdioxide, orange flavour and sucrose. The sucrose content in thiscomposition, depending on the active substance dosage, changes between56 and 76% as weight of the total composition.

Another Spanish patent application, ES 2020790 (Zambon Group, S.p.a.),discloses a granulated containing fosfomycin trometamol, saccharine,flavour and sucrose. The sucrose content in this composition comprises28% as weight of the total composition.

The Spanish patent application ES2224869 (Zambon Group, S.p.a.)discloses the use of certain basic compounds to stabilize a fosfomycintrometamol pharmaceutical composition. Some compositions described inthe examples also mention the use of between 16% and 22% of sucrose asweight of the total composition.

The Spanish patent application ES2244333 (Simbec Ibérica, S. L.)discloses a pharmaceutical preparation comprising fosfomycin trometamol,mannitol and/or xylitol and an artificial sweetening agent selected fromthe group including acesulfame, aspartame, saccharin, alitame and/orcyclamate. The mannitol and/or xylitol content comprises between 20-40%as weight of the total composition.

The presence of certain sugars such as sucrose, fructose or glucose in afosfomycin trometamol pharmaceutical composition can arise in anundesirable colouration due to the reaction between the aldehyde groupsof such sugars with the trometamol amine or any other primary aminogroup present in the composition. Furthermore, the presence of thesesugars makes the obtained pharmaceutical composition not suitable forthe administration to diabetic patients.

On the other hand, it is well known in the state of the art thatpharmaceutical compositions comprising a sugar derivative such as asugar alcohol, in particular xylitol, mannitol, sorbitol or mixturesthereof, can cause intestinal problems such as an undesirable laxativeeffect or abdominals gases.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a stable solid fosfomycinpharmaceutical composition for oral administration characterised bycomprising fosfomycin trometamol, glycine, optionally otherpharmaceutically acceptable excipients, and it is substantially freefrom sugars and sugar alcohols such as sucrose, fructose, glucose,xylitol, mannitol, sorbitol or mixtures thereof.

By the term “substantially free” it is understood that the sugar orsugar alcohol content is non-existent or so low that fosfomycinpharmaceutical composition of the invention still is stable fromcolouration, suitable for diabetics and no cause intestinal problems.

Glycine is a neutral amino acid with a pH value between 5.9 and 6.4according to the European Pharmacopoeia 6.0. Glycine does not have anylateral chain; it is the unique amino acid without chiral centre.

This amino acid has a slight sweet taste that, different from otheramino acids with bitter or acid taste, makes it suitable to be used as adiluent in an oral administration pharmaceutical composition.Furthermore, the absence of aldehyde groups on its structure avoids thecoloration due to the Maillard reaction with amines making possible toobtain stable from coloration compositions. At the same time, apharmaceutical composition comprising glycine does not represent anyrisk for diabetic patients because does not give any glycemic response,and no gastrointestinal problems such as an undesirable laxative effector abdominal gases are arisen.

The amount of glycine can be easily determined by a person skilled inthe art in order to get a fosfomycin trometamol solid oralpharmaceutical composition by known techniques usual in the state of theart. Generally, the amount of glycine presents in the fosfomycinpharmaceutical composition can comprise between 0.1 and 70% expressed byweight over the composition total weight. Preferably, the amount ofglycine comprises between 20 and 50% as weight of the total composition.

Optionally, this fosfomycin trometamol pharmaceutical compositioncomprises one or more sweeteners to improve its palatability.Preferably, the sweetener is selected from the group includingsucralose, acesulfame, aspartame, saccharine, alitame, cyclamate,neohesperidine dihydrochalcone, thaumatina and mixtures thereof.

More preferably, the sweetener used to improve the palatability of thepharmaceutical composition comprising fosfomycin trometamol and glycineis sucralose. This compound is between 300 and 1000 times sweeter thansucrose, does not have the aftertaste characteristic of other artificialsweeteners, is not absorbed by the organism and does not presenttoxicity problems.

The addition of sucralose to the pharmaceutical composition allowsobtain a more pleasant taste using only a small quantity of such asweetener. The fosfomycin trometamol and glycine pharmaceuticalcomposition of this invention can comprise between 0.0 and 5.0% ofsucralose, preferably between 1.0 and 2.0% as weight of the totalcomposition.

In a preferred embodiment, the fosfomycin pharmaceutical composition ispresented in form of powder or granulates for solution. More preferablythe powder or granulates for solution are contained in single dosagessachets for solution.

Optionally, the fosfomycin pharmaceutical composition further comprisesone or more of other pharmaceutical acceptable excipients usual in thepharmaceutical industry to obtain oral administration solidcompositions, in particular to obtain pharmaceutical compositions inform of powder or granulate for solution.

Preferably these excipients are selected from the group includingglidants such as calcium silicate, magnesium silicate, silicon dioxide,magnesium stearate, magnesium oxide, talc, cellulose, starch or mixturesthereof; binders such as microcrystalline cellulose, pregelatinizedstarch, copovidone, polyvinylpyrrolidone (povidone), hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydrogenated vegetable oil ormixtures thereof; and/or flavours such as orange, tangerine, lemon,raspberry, strawberry or coconut.

More preferably, the fosmomycin trometamol and glycine pharmaceuticalcomposition further comprises sucralose as sweetener, silicon dioxide asglidant, polyvinylpyrrolidone as binder and lemon flavour.

The pharmaceutical composition of this invention generally containsbetween 1.9 and 7.5 g of fosfomycin trometamol, corresponding to 1.0 and4.0 g of fosfomycin expressed as free acid. Preferably, the compositioncontains between 3.8 g and 5.6 g of fosfomycin trometamol, correspondingto 2.0 and 3.0 g of fosfomycin expressed as free acid.

The drug substance amounts previously mentioned corresponds to between30% and 99.9% by weight over the composition total weight. Preferably,the content of fosfomycin trometamol represents between 50% and 80% byweight over the composition total weight.

The fosfomycin stable solid pharmaceutical composition for oraladministration of this invention can be used for the manufacture of amedicament for the treatment or profilaxis of uncomplicated acuteinfections of the lower urinary tract.

Furthermore, the fosfomycin stable solid pharmaceutical composition fororal administration of this invention can be used for the treatment orprofilaxis of uncomplicated acute infections of the lower urinary tract.

The fosfomycin pharmaceutical composition to this invention can beobtained by methods widely known by the person skilled in the art, inparticular by mixing and/or granulation methods.

EXAMPLE Powder or Granulate for Solution

The components are homogeneously mixed and, optionally, granulated byknown techniques usual in the state of the art. The solid obtained isdosed in sachets containing the quantity equivalent to 2.0 g or 3.0 g offosfomycin in acid form.

Fosfomycin trometamol  63% Glycine  32% Sucralose 1.3% Lemon flavour1.4% Silicon dioxide 0.1% Polyvinylpyrrolidone 2.2% Total 100% 

The invention claimed is:
 1. A stable solid fosfomycin pharmaceuticalcomposition for oral administration characterized by comprising a)fosfomycin trometamol, b) glycine and c) optionally other pharmaceuticalacceptable excipients, and it is substantially free from sugars andsugar alcohols.
 2. The pharmaceutical composition according to claim 1,characterized by further comprising a pharmaceutically acceptablesweetener.
 3. The pharmaceutical composition according to claim 2,characterized in that the sweetener is selected from the group includingsucralose, acesulfame, aspartame, saccharine, alitame, cyclamate,neohesperidine dihydrochalcone, thaumatina and mixture thereof.
 4. Thepharmaceutical composition according to claim 3, characterised in thatthe sweetener is sucralose.
 5. The pharmaceutical composition accordingto claim 1, characterised by comprising other pharmaceuticallyacceptable excipients.
 6. The pharmaceutical composition according toclaim 1, characterised by comprising, expressed as weight of the totalcomposition: a) between 30% and 99.9% fosfomycin trometamol, b) between0.1 and 70% glycine, and c) optionally other pharmaceutically acceptableexcipients in quantity enough to complete the 100% of the compositiontotal weight.
 7. The pharmaceutical composition according to claim 6,characterised by comprising, expressed as weight of the totalcomposition: a) about 63% fosfomycin trometamol, b) about 32% glycine,and c) optionally other pharmaceutically acceptable excipients inquantity enough to complete the 100% of the composition total weight. 8.The pharmaceutical composition according to claim 6, characterised bycomprising, expressed as weight of the total composition: a) between 30%and 99.9% fosfomycin trometamol, b) between 0.1 and 70% glycine, c)between 0.0 and 5.0% sweetener, and d) optionally other pharmaceuticallyacceptable excipients in quantity enough to complete the 100% of thecomposition total weight.
 9. The pharmaceutical composition according toclaim 7, characterised by comprising, expressed as weight of the totalcomposition: a) about 63% fosfomycin trometamol, b) about 32% glycine,c) about 1.3% sucralose, d) about 0.1% silicon dioxide, e) about 2.2%polyvinylpyrrolidone, and f) about 1.4% lemon flavour.
 10. Thepharmaceutical composition according to claim 8, characterised in beingpowder or granulate for solution.
 11. The pharmaceutical compositionaccording to claim 10, characterised in that the powder or granulate forsolution is soluble in water.
 12. A method of treatment and/orprophylaxis of a mammal suffering from or being susceptible touncomplicated acute infections of the lower urinary tract, said methodcomprising the administration to said mammal, of the fosfomycin stablesolid pharmaceutical composition for oral administration as defined inclaim 1.